Our overall objective is to solve the problem of how proteins fold into their native conformations and then (e.g. as enzymes) interact with substrates and other ligands. For this purpose, we are using the methodology of protein chemistry, and developing and applying experimental and theoretical techniques (to be used together) to provide an understanding of the internal interactions which stabilize native proteins in aqueous solution. The experimental work involves the use of immunochemistry, flash photolysis, proteolytic digestion, resonance Raman spectroscopy, and fluorescence energy transfer to determine the pathways of folding or ribonucleases and lysozyme, and the interactions of lysozyme and carboxypeptidase with substrates. The theoretical work involves studies of the hydration of peptide-like model compounds, and the incorporation of these results, together with empirical potentials, in various computational approaches to study the interactions involved in protein folding (e.g. bovine pancreatic trypsin inhibitor) and in formation of enzyme-substrate complexes (e.g. lysozyme plus hexasaccharide copolymer). An understanding of the interactions in proteins is of potential applicability to the elucidation of the role of conformation in biological processes, e.g. the undersirable association of sickle-cell hemoglobin.